Process for synthesising useful intermediates for the preparation of avss3 receptor antagonists
AssigneeMerck Sharp & Dohme Corp.
InventorsBrian Bishop, Karel Marie Brands, Ian Cottrell, Cameron Cowden, Anthony Davies, Stephen Keen, David Lieberman, Gavin Stewart
Life of this patent
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Abstract
The present invention relates to the synthesis of intermediates for the preparation of compounds of formula (A): wherein n is 2 or 3 and various salt forms of these compounds. The compounds of formula (A) are useful as ανβ3 receptor antagonists.
Claims42
A process for the preparation of a compound of formula (I)
- comprising closing the ring of a compound of formula (II)
- wherein R1 is hydrogen, chlorine, bromine or lower alkyl, P is an amino protecting group and n is 2 or 3, and Y is a group selected from chlorine, bromine, iodine, mesylate, tosylate, brosylate, nosylate and triflate.
A process for the preparation of a compound of formula (I)
- wherein R1 is hydrogen, chlorine, bromine or lower alkyl, P is an amino protecting group and n is 2 or 3, comprising
- (a) reacting a compound of formula (III)
- wherein R1 and P are as previously defined and R3 is hydrogen or methyl, with a compound of the formula (IV)
- X—(CH2)m—Y (IV)
- wherein Y is a group selected from chlorine, bromine, iodine, mesylate, tosylate, brosylate, nosylate, and triflate, X is a group selected from a chlorine, bromine, iodine, mesylate, tosylate, brosylate, nosylate, and triflate, and m is 3 or 4 when R3 is hydrogen, or m is 2 or 3 when R3 is methyl, to afford a compound of formula (II)
- and
- (b) closing the ring of the compound of formula (II).
A process for the preparation of the compounds of the formulae (V) and (VI):
- comprising reacting a compound of the formula (VII)
- with an alkyllithium to form a reaction mixture, and
- reacting the reaction mixture with the compound of the formula (IV)
- X—(CH2)m—Y (IV)
- wherein Y is a group selected from a chlorine, bromine, iodine, mesylate, tosylate, brosylate, nosylate, and triflate, X is a group selected from chlorine, bromine, iodine, mesylate, tosylate, brosylate, nosylate, and triflate, and m is 3 or 4, to yield a compound of the formula (VIII)
- wherein Y is as previously defined, and p is 3 or 4, and
- cyclizing the compound of formula VIII, without isolation, to form the compounds of formulae (V) and (VI).
A process for the preparation of compounds of formulae (XIa) and (XIb)
- and salts thereof wherein R is an esterifying group, comprising transforming the anhydride of formula (XII) via asymmetric solvolysis
A process for the preparation of a compound of formula (XIII)
- wherein R is an esterifying group and X is a —CH2P(O)(OR′)2 group, wherein R′ is defined as a C1-6 alkyl group, comprising:
- (i) reacting a compound of formula (XIa)
- with pivaloyl chloride and triethylamine, yielding a compound of formula (XIII) wherein X is —O.CO.C(CH3)3 to form a reaction mixture;
- and
- (ii) reacting the reaction mixture with an excess of lithiated dialkylmethylphosphonate.
A process for the preparation of a compound of formula (XIII)
- wherein R is an esterifying group and X is a Ph3P═CH— group, comprising:
- (i) reacting one of pivaloyl chloride or isobutylchloroformate with a suitable base, yielding compounds of formula (XIII) wherein X is —O.CO.C(CH3)3 and —OCO2iBu, respectively to form a reaction mixture;
- and
- (ii) reacting the reaction mixture with an excess of lithiated Ph3P⊕CH3.Br⊖.
A process for the preparation of a compound of formula (A)
- wherein n is 2 or 3, which comprises reacting a compound of formula (XVI) with a compound of formula (XIII)
- wherein n is 2 or 3, P is an amino protecting group, R is an esterifying group and X is a group selected from CH2P(O)(OR′)2, where R′ is a C1-6 alkyl group or —CH═PPh3 to form an enone;
- and reducing the enone and deprotecting the carboxyl and amino groups.
A process for the preparation of a compound of formula (XVI) which comprises
- (i) reacting a compound of formula (I) with a compound of formula (XIX)
- wherein R1 is a chlorine atom and each Ra is independently C1 to C6 straight or branched alkyl, P is an amino protecting group and n is 2 or 3, in the presence of a catalyst formed in situ from a suitable palladium salt and a ligand, and a base, and
- (ii) hydrolysing the resultant acetal to yield the compound of formula (XVI).
The crystalline zwitterion of the compound of formula (A)
- wherein n=3 characterised by the X-ray powder diffraction data shown in Table 1 and FIG. 3.
The crystalline TRIS salt of the compound of formula (A)
- wherein n=3 characterised by the X-ray powder diffraction data shown in Table 2 and FIG. 4.
Dependencies are inferred from the claim text.